Abstract

Glaucoma is a leading cause of blindness worldwide. Surgical lowering of
intraocular pressure (IOP) is frequently necessary, although scarring causes failure.
Chemotherapeutics applied locally increase success but may have blinding
complications, including hypotony and infections. Modifications in technique
reduce risk, though intense monitoring is required postoperatively.
Matrix metalloproteinase inhibitors (MMPis) may be a less toxic anti-scarring
alternative. Because the inhibition is reversible multiple injections are needed in
experiments to maintain efficacy. Injections are uncomfortable, painful and costly
however. The pharmacokinetic profile also shows concentration spikes and rapid
drug clearance.
A sustained release preparation is therefore desirable. Here we show in chambers
modeling aqueous flow that single pure ilomastat MMPi implants maintained a
therapeutic concentration between 10 and 23 days. In the in vivo model, bleb
survival appeared to be significantly prolonged, however a foreign body reaction
existed to undissolved implants, with significant collagen deposition in the
conjunctiva. To improve efficacy and reduce the proscarring nature of undissolved
drug, implants of the more soluble MMPi marimastat and combination implants of
ilomastat together with hyaluronic acid were formulated. These dissolved faster, but
failed earlier. A combined implant of the anti-inflammatory dexamethasone and
ilomastat appeared to prolong survival with less, but still considerable reaction.
Coating ilomastat implants with a biocompatible polymer caused less reaction, but
inflammatory foci existed around presumed polymer defects. A more hydrophilic
polymer caused less reaction, though with macrophage infiltration.
During these experiments it became apparent that bleb appearance when using
implants did not necessarily correlate with survival. Thus the notion of ‘bleb
survival’ as an outcome was questioned and other outcomes tested. Dye to trace
aqueous movement was too slow. Inducing ocular hypertension in the rabbit caused
only a temporary, unpredictable pressure rise, and buphthalmos. Pooling IOP data
from larger numbers after standard surgery appeared to be most accurate.